Coating method for a folded balloon

ABSTRACT

The present invention relates to compositions which are suitable for selective filling or selective coating of folds of a folded balloon, and especially relates to compositions of a contrast agent and an active agent in a solvent for filling of folds of a folded catheter balloon as well as to methods for selective filling or selective coating of folds of a folded catheter balloon and to filled or coated folded catheter balloons which can be obtained according to one of these methods.

The present invention relates to compositions which are suitable forselective filling or selective coating of folds of a folded balloon, andespecially relates to compositions of a contrast agent and an activeagent in a solvent for filling of folds of a folded catheter balloon aswell as to methods for selective filling or selective coating of foldsof a folded catheter balloon and to filled or coated folded catheterballoons which can be obtained according to one of these methods.

For the treatment of stenoses it is state of the art to implant stentsor to dilatate the narrowed vascular region by so-called biologicalstenting. Therefore often stents and/or catheter balloons are used whichare coated with a polymer as active agent carrier and an anti-restenoticactive agent.

As usually the catheter balloon, with or without a mounted, i.e. crimpedstent, has to pass a longer vessel route to arrive at the site of thevessel narrowing the problem of protecting the active agent againstpremature release from the stent and/or balloon arises.

With respect to stents different solutions for this problem have beenproposed already. For example, US 2004/0071861 and WO 03/035131 Adisclose that in the struts of the stent small cavities for receiving anactive agent can be provided and that the active agent in the cavitiescan be protected by applying a protective coating.

WO 02/45744 A describes a stent without cavities which is provided witha first coating comprising an active agent and a superjacent inelasticcovering layer which protects the active agent. The invention accordingto WO 02/45744 A shall be that upon expansion of the stent the inelasticcovering layer breaks up and releases the active agent selectively atthe site of its purpose.

For catheter balloons such covering layers are also thinkable, however,due to the large surface of the catheter balloon more difficulty torealize as practical embodiments.

The European Patent EP 0 519 063 B1 discloses the possibility of coatinga folded catheter balloon with micro capsules, wherein in the microcapsules a pharmacological active agent can be included. Moreover, EP 0519 063 B1 discloses the possibility of including a part of the microcapsules in the folds of the folded catheter balloon if the foldedcatheter balloon in the expanded, i.e. inflated state, is provided withmicro capsules and then folded again, i.e. deflated (see claim 8 of EP 0519 063 B1).

However, this embodiment has still the problem that only a part of themicro capsules is included in the folds and thus the amount of activeagent which is present in the folds is unknown. The micro capsules whichare not included in the folds are almost completely released from theballoon surface upon inserting the folded catheter balloon and do notarrive at the destination. Moreover, the method of coating according toEP 0 519 063 B1 is restricted to solids and especially to micro capsulesand can not be used with liquids.

The object of the present invention was to apply the active agent in theactive agent application via a catheter balloon in such a way that anundesired premature release does not occur.

The object is solved by providing an active agent-filled folded catheterballoon according to herein described embodiments as well as methods ofcoating as well as a composition which is suitable for these methods ofcoating. Further advantages designs, aspects and details of theinvention are in the claims, description, examples and figures.

The object is solved by providing of methods of coating which coat thefolded catheter balloon in the compressed or only minimally inflatedstate.

Thereby the amount of active agent within the folds is exactly knownwhat is an important aspect for clinical approvals and additionally theactive agents can be conveniently inserted in a dissolved form without aprior complicated provision of special pharmacological formulations suchas micro capsules.

The methods of coating according to the invention are selectivelycoating the folds, i.e. are selectively filling the folds, wherein theremaining balloon surface which is not under the folds remains uncoated.

The selective filling of the folds is done via so-called punctual orlinear coating methods. Not used are methods of dipping or sprayingwhich cover the whole balloon surface. Moreover, the methods accordingto the invention are used with deflated and compressed or slightlyinflated folded catheter balloons.

According to the invention a pipetting method is used which utilizes thecapillary forces, a syringe method is used wherein a precision nozzle ismoved relative to the longitudinal direction of the fold, or a sprayingmethod is used wherein one or more precision nozzles being in series areinserted under the fold and which fill the fold at one or more pointsuntil the fold is completely filled.

Basically, in the methods according to the invention each fold is filledor coated separately. Before the next fold is filled or coated thecontent of the first fold can be dried, however, this is not necessaryin each case. It is also possible to fill resp. to coat all of the foldssequentially and then to dry the content of all of the folds.

According to the invention drying is done under rotating the foldedcatheter balloon which is described in detail below.

Coating or filling of the folds is done with a liquid mixture comprisingat least one active agent and a solvent or carrier. Moreover, alsocontrast agents, salts, adjuvants or other pharmacologically acceptablesubstances can be present.

As active agent any antiproliferative, antiinflammatory, antiphlogistic,cytostatic, cytotoxic, antiangiogenic, anti-restenotic or antithromboticactive agent can be used.

Examples of such active agents are abciximab, acemetacin, acetylvismioneB, aclarubicin, ademetionine, adriamycin, aescin, afromoson, akagerine,aldesleukin, amidorone, aminoglutethemide, amsacrine, anakinra,anastrozole, anemonin, anopterine, antimycotics, antithrombotics,apocymarin, argatroban, aristolactam-AII, aristolochic acid, ascomycin,asparaginase, aspirin, atorvastatin, auranofin, azathioprine,azithromycin, baccatine, bafilomycin, basiliximab, bendamustine,benzocaine, berberine, betulin, betulinic acid, bilobol, biolimus,bisparthenolidine, bleomycin, bombrestatin, Boswellic acids andderivatives thereof, bruceanoles A, B and C, bryophyllin A, busulfan,antithrombin, bivalirudin, cadherins, camptothecin, capecitabine,o-carbamoyl-phenoxy-acetic acid, carboplatin, carmustine, celecoxib,cepharanthin, cerivastatin, CETP inhibitors, chlorambucil, chloroquinephosphate, cictoxin, ciprofloxacin, cisplatin, cladribine,clarithromycin, colchicine, concanamycin, coumadin, C-type NatriureticPeptide (CNP), cudraisoflavone A, curcumin, cyclophosphamide,cyclosporine A, cytarabine, dacarbazine, daclizumab, dactinomycin,dapson, daunorubicin, diclofenac, 1,11-dimethoxycanthin-6-one,docetaxel, doxorubicin, daunomycin, epirubicin, epothilones A and B,erythromycin, estramustine, etoposide, everolimus, filgrastim,fluoroblastin, fluvastatin, fludarabine,fludarabine-5′-dihydrogenphosphate, fluorouracil, folimycin, fosfestrol,gemcitabine, ghalakinoside, ginkgol, ginkgolic acid, glycoside 1a,4-hydroxyoxycyclophosphamide, idarubicin, ifosfamide, josamycin,lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone,nimustine, pitavastatin, pravastatin, procarbazin, mitomycin,methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan,topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase,exemestane, letrozole, formestane, SMC proliferation inhibitor-2ω,mitoxantrone, mycophenolate mofetil, c-myc antisense, b-myc antisense,β-lapachone, podophyllotoxin, podophyllic acid 2-ethylhydrazide,molgramostim (rhuGM-CSF), peginterferon α-2b, lanograstim (r-HuG-CSF),macrogol, selectin (cytokine antagonist), cytokinin inhibitors, COX-2inhibitor, NFkB, angiopeptin, monoclonal antibodies which inhibit themuscle cell proliferation, bFGF antagonists, probucol, prostaglandins,1-hydroxy-11-methoxycanthin-6-one, scopoletin, NO donors,pentaerythritol tetranitrate, sydnonimines, S-nitrosoderivatives,tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone,ethinylestradiol, medroxyprogesterone, estradiol cypionates, estradiolbenzoates, tranilast, kamebakaurin and other terpenoids which areapplied in the therapy of cancer, verapamil, tyrosine kinase inhibitors(tyrphostins), paclitaxel, derivatives and analoga of paclitaxel,6-α-hydroxy-paclitaxel, 2′-succinylpaclitaxel,2′-succinylpaclitaxeltriethanolamine, 2′-glutarylpaclitaxel,2′-glutarylpaclitaxeltriethanolamine, 2′-O-ester of paclitaxel withN-(dimethylaminoethyl)glutamide, 2′-O-ester of paclitaxel withN-(dimethylaminoethyl)glutamidhydrochloride, taxotere, macrocyclicoligomers of carbon suboxide (MCS), mofebutazone, lonazolac, lidocaine,ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine,hydroxychloroquine, sodium aurothiomalate, oxaceprol, β-sitosterin,myrtecaine, polidocanol, nonivamide, levomenthol, ellipticine, D-24851(Calbiochem), colcemid, cytochalasin A-E, indanocine, nocadazole, S 100protein, bacitracin, vitronectin receptor antagonists, azelastine,guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and-2, free nucleic acids, nucleic acids incorporated into virustransmitters, DNA and RNA fragments, plasminogen activator inhibitor-1,plasminogen activator inhibitor-2, antisense oligonucleotides, VEGFinhibitors, IGF-1, active agents from the group of antibiotics,cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamycin,penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole,enoxaparin, desulphated and N-reacetylated heparin, tissue plasminogenactivator, GpIIb/IIIa platelet membrane receptor, factor Xa inhibitorantibody, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase,streptokinase, warfarin, urokinase, vasodilators, dipyridamol, trapidil,nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACEinhibitors, captopril, cilazapril, lisinopril, enalapril, losartan,thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ,histamine antagonists, serotonin blockers, apoptosis inhibitors,apoptosis regulators, p65, NF-kB, Bcl-xL antisense oligonucleotides,halofuginone, nifedipine, tocopherol, tranilast, molsidomine, teapolyphenols, epicatechin gallate, epigallocatechin gallate, leflunomide,etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline,triamcinolone, mutamycin, procainimide, retinoic acid, quinidine,disopyramide, flecainide, propafenone, sotolol, natural andsynthetically obtained steroids, inotodiol, maquiroside A,ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone,dexamethasone, non-steroidal substances (NSAIDS), fenoprofen, ibuprofen,indomethacin, naproxen, phenylbutazone, antiviral agents, ayclovir,ganciclovir, zidovudin, clotrimazole, flucytosine, griseofulvin,ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents,chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin,barringtogenol-C21-angelat, 14-dehydroagrostistachin, agroskerin,agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,4,7-oxycycloanisomel acid, baccharinoids B1, B2, B3 and B7, tubeimoside,bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin,tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptaticacid A, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A andB, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B,13,18-dehydro-6-alpha-senecioyloxychaparrin, taxamairin A and B,regenilol, triptolide, cymarin, hydroxyanopterin, protoanemonin,cheliburin chloride, sinococuline A and B, dihydronitidine, nitidinechloride, 12-beta-hydroxypregnadien-3,20-dion, helenalin, indicine,indicine-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin Aand B, larreatin, malloterin, mallotochromanol,isobutyrylmallotochromanol, maquiroside A, marchantin A, maytansin,lycoridicin, margetine, pancratistatin, liriodenine, bisparthenolidine,oxoushinsunine, periplocoside A, ursolic acid, deoxypsorospermin,psycorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin,sphatheliachromen, stizophyllin, mansonine, strebloside,dihydrousambaraensine, hydroxyusambarine, strychnopentamine,strychnophylline, usambarine, usambarensine, liriodenine,oxoushinsunine, daphnoretin, lariciresinol, methoxylariciresinol,syringaresinol, sirolimus, rapamycin, somatostatin, tacrolimus,roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine,vincristine, vindesine, teniposide, vinorelbine, trofosfamide,treosulfan, temozolomide, thiotepa, tretinoin, spiramycin,umbelliferone, desacetylvismione A, vismione A and B, zeorin as well asmixtures of said active agents.

Especially preferred active agents are rapamycin (sirolimus) andpaclitaxel, derivatives and analogues of paclitaxel,6-α-hydroxy-paclitaxel, 2′-succinylpaclitaxel,2′-succinylpaclitaxeltriethanol-amine, 2′-glutarylpaclitaxel,2′-glutarylpaclitaxeltriethanolamine, 2′-O-ester of paclitaxel withN-(dimethylaminoethyl)glutamide, 2′-O-ester of paclitaxel withN-(dimethylaminoethyl)glutamidehydrochloride, taxotere as well asmixtures of said active agents. Especially preferred is paclitaxel.

Of course, also active agent mixtures can be used, such as an activeagent mixture of paclitaxel and trapidil or of paclitaxel with anNO-donor or of rapamycin with vitamin A or vitamin C.

Also important is the used solvent which is removed by drying atatmospheric pressure or under vacuum after filling the folds.

As solvents lightly volatile organic compounds such as dichloromethane,chloroform, ethanol, acetone, heptane, n-hexane, DMF, DMSO, methanol,propanol, tetrahydrofurane (THF), methylenechloride, ethers,petrolether, acetic acid ester, cyclohexane can be used. In theselection of the solvent it is particularly important that it does notattack resp. renders the material of the folded catheter balloonunusable resp. that the contacting time of the solvent is such shortthat no damaging occurs resp. that an eventual damaging is irrelevantand does not result in damages which could lead to bursting of theballoon during dilatation.

As solvents preferably alcohols and especially diols and triols also incombination with monools have proved of value. The preferred solvent canespecially selected from the following group: methanol, ethanol,isopropanol, n-butanol, iso-butanol, t-butanol, ethyleneglycol,propyleneglycol, 1,3-propanediol, butyleneglycol, 1,3-butanediol,1,4-butanediol, glycerin, 1,2,3-butanetriol, 1,2,4-butanetriol and1,2,3,4-butanetetraol, wherein also mixtures of these solvents as wellas mixtures of the above mentioned organic solvents can be used.Preferred are ethyleneglycol, propyleneglycol, 1,3-propanediol,butyleneglycol, 1,3-butanediol, 1,4-butanediol and especially preferredis glycerin.

Also water can be contained in the solvent mixture, however, preferablyin an amount lower than 50% by weight, preferred 30% by weight andespecially preferred 10% by weight with respect to the total solution.

Depending on the method of coating according to the invention thinviscous solutions of the active agent of thick viscous solutions of theactive agent or active agent combination are required.

Viscosity measurements are known by a skilled person and are preferablydone with viscosimeters. The viscosity has to be adjusted according tothe type and design of the folds.

Different types of folds and embodiments of folded catheter balloons aredisclosed for example in EP 0 519 063 B1, WO 94/23787 A1 or WO 03/059430A1. However, as almost every catheter balloon which can be deflatedresp. dilated has folds the coating methods according to the inventioncan be used basically with every inflatable catheter balloon and are notrestricted to the special embodiments mentioned in WO 94/23787 A1 or WO03/059430 A1.

As solvents can be used besides of the above mentioned or together withthe above mentioned solvents also oils, fatty acids and fatty acidesters. Preferred oils are for example: linseed oil, flax oil, hempseedoil, corn oil, walnut oil, rape oil, soy bean oil, sun flower oil,poppy-seed oil, safflower oil, wheat germ oil, safflower oil, grape-seedoil, evening primrose oil, borage oil, black cumin oil, algae oil, fishoil, cod-liver oil and/or mixtures of said oils.

Undiluted oils are used as solvents in the event when a thick viscouscoating solution is required. By adding lipophilic solvents theviscosity can be lowered and thus a desired viscosity level can beadjusted. On the other hand thin viscous solutions can be increased intheir viscosity by adding oils or fats.

The term “solution” or “coating solution” as used herein shall not onlyrelate to clear solutions but also emulsions, dispersions andsuspensions of one or more active agents in a solvent or solvent mixtureoptionally with other carriers, adjuvants or for example contrastagents.

The term “composition” or “active agent-containing composition” as usedherein shall not only relate to solutions but also emulsions,dispersions, suspensions, oils, pastes, and viscous mixtures containingat least one pharmacological active agent. However, these compositionsare not solid but liquid to viscous or in the form of a gel or paste.

As oils or basically as lipophilic substances natural and syntheticoils, fats, lipids, lipoids and waxes can be used.

WO 03/022265 A1 describes for example oily formulations of paclitaxelwhich can be used also and which are preferred. Comparable solutions ofoils can be made also with other active agents such as trapidil orrapamycin.

Further examples for suitable oils or lipophilic substances can berepresented by the following general formulae:

whereinR, R′, R″, R* and R** are independently of each other alkyl, alkenyl,alkinyl, heteroalkyl, cycloalkyl, heterocyclyl groups having 1 to 20carbon atoms, aryl, arylalkyl, alkylaryl, heteroaryl groups having 3 to20 carbon atoms or functional groups and preferably represent thefollowing groups: —H, —OH, —OCH₃, —OC₂H₅, —OC₃H₇, —O-cyclo-C₃H₅,—OCH(CH₃)₂, —OC(CH₃)₃, —OC₄H₉, —OPh, —OCH₂-Ph, —OCPh₃, —SH, —SCH₃,—SC₂H₅, —NO₂, —F, —Cl, —Br, —I, —CN, —OCN, —NCO, —SCN, —NCS, —CHO,—COCH₃, —COC₂H₅, —COC₃H₇, —CO-cyclo-C₃H₅, —COCH(CH₃)₂, —COC(CH₃)₃,—COOH, —COOCH₃, —COOC₂H₅, —COOC₃H₇, —COO-cyclo-C₃H₅, —COOCH(CH₃)₂,—COOC(CH₃)₃, —OOC—CH₃, —OOC—C₂H₅, —OOC—C₃H₇, —OOC-cyclo-C₃H₅,—OOC—CH(CH₃)₂, —OOC—C(CH₃)₃, —CONH₂, —CONHCH₃, —CONHC₂H₅, —CONHC₃H₇,—CON(CH₃)₂, —CON(C₂H₅)₂, —CON(C₃H₇)₂, —NH₂, —NHCH₃, —NHC₂H₅, —NHC₃H₇,—NH-cyclo-C₃H₅, —NHCH(CH₃)₂, —NHC(CH₃)₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(C₃H₇)₂,—N(cyclo-C₃H₅)₂, —N[CH(CH₃)₂]₂, —N[C(CH₃)₃]₂, —SOCH₃, —SOC₂H₅, —SOC₃H₇,—SO₂CH₃, —SO₂C₂H₅, —SO₂C₃H₇, —SO₃H, —SO₃CH₃, —SO₃C₂H₅, —SO₃C₃H₇, —OCF₃,—OC₂F₅, —O—COOCH₃, —O—COOC₂H₅, —O—COOC₃H₇, —O—COO-cyclo-C₃H₅,—O—COOCH(CH₃)₂, —O—COOC(CH₃)₃, —NH—CO—NH₂, —NH—CO—NHCH₃, —NH—CO—NHC₂H₅,—NH—CO—N(CH₃)₂, —NH—CO—N(C₂H₅)₂, —O—CO—NH₂, —O—CONHCH₃, —O—CONHC₂H₅,—O—CO—NHC₃H₇, —O—CO—N(CH₃)₂, —O—CO—N(C₂H₅)₂, —O—CO—OCH₃, —O—CO—OC₂H₅,—O—CO—OC₃H₇, —O—CO—O-cyclo-C₃H₅, —O—CO—OCH(CH₃)₂, —O—CO—OC(CH₃)₃, —CH₂F,—CHF₂, —CF₃, —CH₂Cl, —CH₂Br, —CH₂I, —CH₂—CH₂F, —CH₂—CHF₂, —CH₂—CF₃,—CH₂—CH₂Cl, —CH₂—CH₂Br, —CH₂—CH₂I, —CH₃, —C₂H₅, —C₃H₇, -cyclo-C₃H₅,—CH(CH₃)₂, —C(CH₃)₃, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, -Ph, —CH₂-Ph,—CPh₃, —CH═CH₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C₂H₄—CH═CH₂,—CH═C(CH₃)₂, —C≡CH, —C≡C—CH₃, —CH₂—C≡CH;X is an ester group or amide group and especially —O-alkyl, —O—CO-alkyl,—O—CO—O-alkyl, —O—CO—NH-alkyl, —O—CO—N-dialkyl, —CO—NH-alkyl,—CO—N-dialkyl, —CO—O-alkyl, —CO—OH, —OH;m, n, p, q, r, s and t are independently of each other integers from 0to 20, preferred from 0 to 10.

The term “alkyl” for example in —CO—O-alkyl is preferably one of thealkyl groups mentioned for the aforesaid groups R, R′ etc., such as—CH₂-Ph. The compounds of the aforesaid general formulae can be presentalso in the form of their salts as racemates or diastereomeric mixtures,as pure enantiomers or diastereomers as well as mixtures or oligomers orcopolymers or block copolymers. Moreover, the aforesaid substances canbe used in mixture with other substances such as biostable andbiodegradable polymers and especially in mixture with the hereinmentioned oils and/or fatty acids. Preferred are such mixtures andindividual substances which are suitable for polymerization, especiallyfor auto polymerization.

Preferred are however naturally occurring oils, fatty acids and fattyacid esters, such as oleic acid, eicosapentaenoic acid, timnodonic acid,docosahexaenoic acid, arachidonic acid, linoleic acid, α-linolenic acid,γ-linolenic acid as well as mixtures and esters of said fatty acids.Especially preferred are omega-9 fatty acids, omega-3 fatty acids andomega-6 fatty acids as well as their esters and mixtures containingthese substances preferably with a weight proportion of at least 10% byweight.

Further suitable fatty acids are listed in tables 1 to 4.

TABLE 1 Monoolefinic fatty acids Systematic name Trivial name Short formcis-9-tetradecenoic acid myristoleic acid 14:1(n-5) cis-9-hexadecenoicacid palmitoleic acid 16:1(n-7) cis-6-octadecenoic acid petroselinicacid 18:1(n-12) cis-9-octadecenoic acid oleic acid 18:1(n-9)cis-11-octadecenoic acid vaccenic acid 18:1(n-7) cis-9-eicosenoic acidgadoleinic acid 20:1(n-11) cis-11-eicosenoic acid gondoinic acid20:1(n-9) cis-13-docosenoic acid erucinic acid 22:1(n-9)cis-15-tetracosenoic acid nervonic acid 24:1(n-9) t9-octadecenoic acidelaidinic acid t11-octadecenoic acid t-vaccenic acid t3-hexadecenoicacid trans-16:1 (n-13)

TABLE 2 Poly-unsaturated fatty acids Systematic name Trivial name Shortform 9,12-octadecadienoic acid linoleic acid 18:2(n-6)6,9,12-octadecatrienoic acid γ-linolenic acid 18:3(n-6)8,11,14-eicosatrienoic acid dihomo-γ-linolenic 20:3(n-6) acid5,8,11,14-eicosatetraenoic acid arachidonic acid 20:4(n-6)7,10,13,16-docosatetraenoic acid — 22:4(n-6)4,7,10,13,16-docosapentaenoic — 22:5(n-6) acid 9,12,15-octadecatrienoicacid α-linolenic acid 18:3(n-3) 6,9,12,15-octadecatetraenoic acidstearidonic acid 18:4(n-3) 8,11,14,17-eicosatetraenoic acid — 20:4(n-3)5,8,11,14,17-eicosapentaenoic acid EPA 20:5(n-3)7,10,13,16,19-docosapentaenoic DPA 22:5(n-3) acid4,7,10,13,16,19-docosahexaenoic DHA 22:6(n-3) acid 5,8,11-eicosatrienoicacid meadic acid 20:3(n-9) 9c,11t,13t-eleostearinoic acid8t,10t,12c-calendinoic acid 9c,11t,13c-catalpicoic acid4,7,9,11,13,16,19-docosahepta- stellaheptaenic decanoic acid acidtaxolic acid all-cis-5,9-18:2 pinolenic acid all-cis-5,9,12- 18:3sciadonic acid all-cis-5,11,14- 20:3

TABLE 3 Acetylenic fatty acids Systematic name Trivial name6-octadecynoic acid taririnic acid t11-octadecen-9-ynoic acidsantalbinic or ximeninic acid 9-octadecynoic acid stearolinic acid6-octadecen-9-ynoic acid 6,9-octadeceninic acid t10-heptadecen-8-ynoicacid pyrulinic acid 9-octadecen-12-ynoic acid crepenynic acidt7,t11-octadecadiene-9-ynoic acid heisterinic acidt8,t10-octadecadiene-12-ynoic acid — 5,8,11,14-eicosatetraynoic acidETYA

TABLE 4 Saturated fatty acids Systematic name Trivial name Short formdodecanoic acid laurinic acid 12:0 tetradecanoic acid myristinic acid14:0 hexadecanoic acid palmitinic acid 16:0 heptadecanoic acidmargarinic acid 17:0 octadecanoic acid stearinic acid 18:0 eicosanoicacid arachinic acid 20:0 docosanoic acid behenic acid 22:0 tetracosanoicacid lignocerinic acid 24:0

Moreover, the esters of the fatty acids listed in tables 1-4 andespecially their ethyl esters and mixtures containing these fatty acidsand/or fatty acid esters are preferred. Further preferred fatty acidsare 6,8-dithianoctanoic acid, γ-linolenic acid and α-liponic acid aswell as their esters.

Moreover, also contrast agents can be included as additional substancesin the composition which is to be inserted.

As matrix for receiving the active agent in the folds of the catheterballoon low molecular substances and especially contrast agents,contrast agent analogues or contrast agent-like substances have provedas suitable. As contrast agent analogues or contrast agent-likesubstances those substances are understood which are not entitled withthe term “contrast agent” but have the characteristics of a contrastagent, namely to be visualized by imaging methods and diagnosis methods.With these substances mostly substances are concerned which containbarium, iodine, manganese, iron, lanthanum, cerium, praseodymium,neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium,erbium, thulium, ytterbium and/or lutetium.

As contrast agents common contrast agents for x-ray imaging, computertomography (CT), magnetic resonance imaging or magnetic resonancetomography (MRT) can be used.

In principle, contrast agents are to be distinguished which are used inx-ray examinations (x-ray contrast agents) and those which are used inmagnetic resonance tomography examinations (MR contrast agents), whereinthe x-ray contrast agents such as Jod-Lipiodol® are preferred.

In the case of x-ray contrast agents substances are concerned whichresult in an increased absorption of penetrating x-rays with respect tothe surrounding structure (so-called positive contrast agents) or whichlet pass penetrating x-rays unhindered (so-called negative contrastagents).

Moreover, iodine-containing contrast agents are preferred which are usedin imaging of vessels (angiography and phlebography) and in CT (computertomography).

Especially preferred are contrast agents having a 1,3,5-triiodobenzenenucleus, nephrotropic x-ray contrast agents having low osmolarity,amidotrizoic acid, iothalaminic acid, iotrolan, iopamidol, iodoxaminicacid, diatrizoic acid, iomeprol, iopromid, desmethoxyacetyl-iopromid(DAMI) or 5-amino-2,4,6-triiodophthalic acid-(2,3-dihydroxypropyl)-amide(ATH).

In the following some structures of the especially preferred contrastagents are shown:

5-amino-2,4,6-triiodophthalic acid-(2,3-dihydroxypropyl)-amide (ATH)

Another class of preferred contrast agents is represented by theparamagnetic contrast agents which contain mostly a lanthanide.

One of the paramagnetic substances which have unpaired electrons is e.g.gadolinium (Gd³⁺) which has in total seven unpaired electrons. Furtherin this group are europium (Eu²⁺, Eu³⁺), dysprosium (Dy³⁺) and holmium(Ho³⁺). These lanthanides can be used also in chelated form by using forexample hemoglobin, chlorophyll, polyaza acids, polycarboxylic acids andespecially EDTA, DTPA as well as DOTA as chelator. Examples ofgadolinium-containing contrast agents are gadoliniumdiethylenetriaminepentaacetic acid, gadopentetic acid (GaDPTA),gadodiamide, meglumin-gadoterate or gadoteridol.

According to the invention of course mixtures of two or more contrastagents can be used.

Moreover, physiologically acceptable salts can be present in thecomposition of the active agent or active agent mixture. Preferred aresolutions or dispersions of an active agent, preferably paclitaxel orrapamycin and especially paclitaxel, together with one or morephysiologically acceptable salts.

As salts preferably compounds can be used which contain sodium cations,calcium, magnesium, zinc, iron or lithium cations together withsulphate, chloride, bromide, iodide, phosphate, nitrate, citrate oracetate anions. As salts also ionic contrast agents can be used or ioniccontrast agents can be added to the above mentioned salts.

To such a solution, dispersion or slurry the active agent or the activeagent combination is added. As solvent preferably water is used,eventually with co-solvents. The salt content should be relatively high.In such salt solutions the main solvent is the water which can containfrom up to 30% by weight, preferred 20% by weight and especiallypreferred up to a maximum of 10% by weight also one or more co-solvents.

Such salt solutions are mostly used for the syringe method.

This salt solution with active agent is syringed under the folds of thefolded catheter balloon and is dried. The salt coating is veryhygroscopic and thus has a high affinity to vessel tissue. Duringdilatation the folds open themselves and press the salty coating againstthe vessel wall. The salt coating then adheres to the vessel wall whereit serves several purposes. On the one hand the local very high saltconcentration results in a high isotonic pressure which bursts cells andon the other hand the high salt concentration dissolves also hard plaqueand other depositions in the vessel and moreover releases the activeagent which especially prevents the proliferation of smooth musclecells.

After a few minutes up to a maximum of a couple of hours, depending onthe amount, the salt coating transferred onto the vessel wall iscompletely dissolved.

Instead of or in combination with the aforementioned salts also aminoacids, oligopeptides, polyamino acids, peptides and/or vitamins can beused.

Suitable amino acids are: glycine, alanine, valine, leucine, isoleucine,serine, threonine, phenylalanine, tyrosine, tryptophane, lysine,arginine, histidine, aspartate, glutamate, aspartic acid, glutamine,cysteine, methionine, proline, 4-hydroxyproline, N,N,N-trimethyllysine,3-methylhistidine, 5-hydroxylysine, O-phosphoserine, γ-carboxyglutamate,ε-N-acetyllysine, ω-N-methylarginine, citrulline, ornithine andderivatives of these amino acids.

Suitable vitamins comprise: vitamin A, vitamin C (ascorbic acid),vitamin D, vitamin H, vitamin K, vitamin E, vitamin B1, vitamin B2,vitamin B3, vitamin B5, vitamin B6, vitamin B12, thiamine, riboflavin,niacin, pyridoxine and folic acid.

Moreover, also liposomal formulations of the active agent or activeagent mixture can be used for the coating resp. filling of foldedcatheter balloons.

The liposomal formulations are preferably manufactured in that in afirst step the active agent (e.g. paclitaxel or rapamycin) resp. theactive agent combination is dissolved in an aqueous medium or buffermedium and then contacted with solutions which contain membrane-formingsubstances. With this method high insertion rates from at least 30% upto 95% result.

Membrane-forming substances are charged amphiphilic compounds preferablyalkylcarboxy acids, alkylsulphonic acids, alkylamines, alkylammoniumsalts, phosphoric acid esters with alcohols, natural as well assynthetic lipids, such as phosphatidylglycerol (PG), phosphatidylserine(PS), derivatives of phophatidylethanolamine (PE derivatives) as well asof cholesterol, phosphatidic acid, phosphatidylinositol, cardiolipin,sphingomyelin, ceramide in its natural, semi-synthetic or syntheticforms, stearylamine and stearic acid, palmitoyl-D-glucuronid and/orcharged sphingolipids, such as sulphatide.

As neutral membrane-forming substances known components can be used,such as phosphatidylcholine (PC), phophatidylethanolamine (PE),steroids, preferably cholesterol, complex lipids and/or neutralsphingolipids.

The extraction of the liposomes from the aqueous solution is also doneaccording to known methods, such as by dialysis, ultra filtration, gelfiltration, sedimentation or flotation. The liposomes have an averagediameter from 10 to 400 nm.

Such liposomal formulations can be preferably inserted into the folds ofa folded catheter balloon via syringe method or capillary method(pipetting method).

The method of coating folds or method of filling folds according to theinvention are the pipetting method also referred to as capillary method,the syringe method and the spraying method also referred to as method ofspraying folds such as to clarify the difference to the unselectivespraying method for the whole catheter balloon.

Thus, the present invention relates to methods of coating or filling thefolds of a folded catheter balloon in the following way:

-   -   a) an active agent-containing composition is delivered at the        distal or proximal end of a fold of the folded catheter balloon        and the fold is filled due to capillary forces; or    -   b) a syringe which delivers a continuous flow of an active        agent-containing composition is moved relative to the folded        catheter balloon along the fold; or    -   c) a plurality of delivery openings being in series are pushed        under the fold of the folded balloon and an active        agent-containing composition is delivered simultaneously from        the plurality of delivery openings into the fold.

It is advantageous that this coating or filling method is preferablyperformed in the compressed or deflated state or at maximum 10% inflatedstate of the catheter balloon. Under the term “10% inflated state” it isto be understood that the catheter balloon was subjected to 10% ofinflation, i.e. the expansion, of the maximum expansion which is plannedin the dilatation. If the expansion which is planned in the dilatationis referred to as 100% and the deflated state is set to 0% then a 10%inflation results according to the following formula:(diameter of the catheter balloon in the deflated state)+(diameter ofthe catheter balloon in the inflated state−diameter of the catheterballoon in the deflated state)/10

Moreover, by the methods according to the invention more or all of thefolds can be coated of filled simultaneously and the coating or fillingcan be done selectively. A selective filling of the folds or selectivecoating of the folds shall mean that only the folds are filled or coatedand the surface of the folded catheter balloon outside the folds is notcoated.

A preferably used composition of active agent, solvent and contrastagent has the consistency of a paste or of a viscous mass or a viscousdispersion or emulsion or a tenacious pulp.

This composition has the advantage that it does not polymerize and thatit maintains its consistency during the coating operation. This paste or(high) viscous mass or viscous slurry is inserted under pressure intothe folds via a syringe device, preferably a nozzle, such as shown inFIG. 1.

If necessary, the nozzle can dilate the balloon folds and selectivelyfill the cavities formed by the folds. Usually the folded catheterballoons have 4 or more folds which are filled individually.

It was proven as especially advantageous to rotate the folded catheterballoon in the direction of the openings of the folds after filling ofone or more or of all of the folds. This rotation results in that theviscous paste is dispersed completely and homogeneously in the folds andthat eventual inclusions of air are released. The rotational directionis shown in FIG. 2. After rotation of the folded catheter balloonanother filling of already filled or empty folds can be done.

During and/or after the rotation the composition in the folds driesunder atmospheric pressure or under reduced pressure. Drying or curingof the composition is done by removing of the at least one alcohol byevaporation. The dried composition has a porous consistency and isreleased very easily from the balloon surface during dilatation. Thealcohol as solvent was removed up to the usual residues and the contrastagent forms a porous matrix for the active agent and is moreover capableof releasing the active agent rapidly and in high concentration afterdilatation of the folded catheter balloon. Moreover, the methodaccording to the invention has the advantage to operate in a verymaterial conserving way as only the folds are coated or filled and thusno active agent is present on the outer balloon surface which is lostduring insertion of the catheter.

In the following the three coating and filling methods according to theinvention are described in more detail.

Pipetting Method or Capillary Method:

In this method a pipette or syringe or another device capable ofpunctual delivery of the active agent-containing composition is used.

Under the term “active agent-containing composition” as used herein themixture of active agent and solvent and/or adjuvant and/or carrier isunderstood, i.e. a real solution, dispersion, suspension or emulsion ofan active agent or an active agent mixture and at least one furthercomponent selected from the herein mentioned solvents, oils, fattyacids, fatty acid esters, amino acids, vitamins, contrast agents, saltsand/or membrane-forming substances. The term “solution” shall furtherclarify that a liquid mixture is concerned which, however, can be alsoviscous (thick viscous or high viscous).

The pipette or syringe or another device capable of punctual delivery ofthe active agent-containing composition is filled with the compositionand preferably set at the proximal or at the distal end of a fold. Thedelivered composition is drawn into the fold and along the fold due tocapillary forces until the opposite end of the fold is reached.

The catheter balloon is in the compressed, i.e. deflated, state. An evenpartial or slight inflation of the catheter balloon is usually notnecessary for opening the folds a little. However, the filling of thefolds can be done with a slight inflation of the catheter balloon ofmaximum 10% of the desired diameter during dilatation. Moreover, thefilling of the folds can be done with a slight expansion of the folds inthat 100 kPa (1 bar) positive pressure, preferred 50 kPa (0.5 bar)positive pressure are applied for slightly expanding the folds.

In this method it is important that the active agent-containingcomposition is sufficiently liquid to generate the respective capillaryforces.

As compositions especially solutions of an active agent or active agentmixture in an alcohol or alcohol mixture are preferred.

The capillary forces should be that strong that a fold having a lengthof 10 mm is completely filled within 5 to 80 seconds, preferred within15 to 60 seconds and especially preferred within 25 to 45 seconds.

If the composition resp. solution is too viscous it can be advantageousto tilt the catheter balloon with the fold to be filled from thehorizontal position upwards for a maximum of 45°, preferred maximum of30° and thereby to utilize also the force of gravity. Usually thefilling of a fold is done via capillary forces, however, in thehorizontal position of the catheter balloon with the fold to be filledupwards. The syringe or pipette or another device capable of punctualdelivery of the active agent-containing composition is preferably set atthe fold at the proximal or at the distal end of the fold sharp in thedirection of the fold devolution in an angle of 10° to 65°, preferred20° to 55°, more preferred in an angle of 27° to 50° and especiallypreferred in an angle of 35° to 45° measured from the horizontal.

Basically there is of course the possibility to set the syringe orpipette or another device capable of punctual delivery of the activeagent-containing composition in the middle of the folds or at any otherpoint located between the distal and proximal ends such that the fold isfilled due to capillary forces simultaneously in the direction of theproximal and the distal ends, however the setting points at the end ofthe fold have proved as preferred.

If the composition for filling the folds resp. the present fold hasreached the opposite end then the substance flow usually stops by itselfand the syringe or pipette or another device capable of punctualdelivery of the active agent-containing composition can be removed.

For not leaving a bigger drop of active agent-containing composition atthe setting point of the syringe or pipette or another device capable ofpunctual delivery of the active agent-containing composition it hasproved as advantageous to already remove the syringe or pipette oranother delivery device before the active agent-containing compositionhas completely reached the other end of the fold. Thereby also theresidual active agent-containing composition remaining at the settingpoint of the syringe or pipette or another delivery device is drawn intothe fold such that no coating composition or filling composition remainsoutside the fold.

Preferably the syringe or pipette or another delivery device is removedwhen about 90% of the fold is filled with active agent-containingcomposition. The optimum point of time for removing the syringe orpipette or another delivery device can be exactly determined by a fewexperiments and is also reproducible.

The term “another device capable of punctual delivery of the activeagent-containing composition” refers to a device which is capable like apipette to deliver a constant and continuous flow of activeagent-containing composition such that under this term a pump, micropump or another reservoir can be understood which ensures this constantand continuous delivery of active agent-containing composition.

After filling a fold the catheter balloon is rotated such that the nextfold to be coated is upwards and preferably horizontally. The fillingoperation of the folds is now repeated.

Depending on the consistency of the active agent-containing compositionit can be necessary to dry the previously filled fold before the balloonis rotated to fill the next fold. Drying is done preferably byevaporation of the solvent.

Moreover, it is also possible in this method to fill or to coatsimultaneously two, more than two or all of the folds of a catheterballoon if the consistency of the active agent-containing compositionenables that, i.e. that the consistency is not that liquid that thecomposition leaks from the folds which are not in horizontal position.

Especially the pipetting method is suitable for the simultaneous fillingor several or all of the folds of a catheter balloon. There the catheterballoon can be positioned horizontal or preferred perpendicular and thedelivery devices are set from above at the ends of the folds preferablyin an angle of 10 to 70 degrees such that the active agent-containingcomposition can flow into the folds.

If all of the folds of the balloon are filled the final drying is done.Basically, it is of course not necessary that all of the folds of thecatheter balloon are filled wherein, however, the filling of all of thefolds is the common and preferred embodiment as during dilatation amaximum possible amount of active agent shall be transferred to thevessel wall in a minimal possible time.

With the folded catheter balloons according to the invention dilatationis done preferably within a maximum of 60 seconds and especiallypreferred within a maximum of 30 seconds.

After filling the last fold drying of the last folds is done, i.e. ofthe content of the last fold, preferably without vacuum under normalpressure by evaporation of the solvent.

After this pre-drying a final drying can be done which is done accordingto the invention with a rotating catheter balloon. If it is necessary ordesired a vacuum can be applied during rotation. This special dryingmethod is described in more detail after the coating methods accordingto the invention.

Spraying Method or Syringe Method:

In this method according to the invention a precision syringe or needleor nozzle is set at the proximal or distal end of a fold and thisdelivery device in the form of a syringe, needle or nozzle is movedalong the longitudinal direction of the fold relative to the fold andper covered partial distance a specified amount of an activeagent-containing composition is delivered.

There, it is not important if the catheter balloon is fixed and thedelivery device moves along the fold of if the delivery device is fixedand the catheter balloon moves relative thereto or if even the catheterballoon and the delivery device move relative to each other. If catheterballoon and delivery device should move relative to each other then amovement on a straight in opposite direction is preferred.

From the delivery device, i.e. syringe, needle or nozzle or the like,preferably a medium or thick viscous active agent-containing compositionis delivered preferably in the form of a paste or a gel or an oil to theinside of the fold. The viscosities of preferred solutions are between10¹ to 10⁶ mPa·s, preferred between 10² to 10⁵ mPa·s and especiallypreferred between 10³ to 10⁴ mPa·s.

Thus, especially suitable as active agent-containing compositions aresuch compositions with the above mentioned oils, alcohols (especiallydiols and polyols), fatty acids, fatty acid esters, amino acids,polyamino acids, membrane-forming substances, liposomal formulationsand/or salts.

In the coating operation the tip of the syringe, nozzle or needlereaches about in the middle of the inside of the fold, thus about intothe middle of the fold. There a continuous flow of the activeagent-containing composition is delivered such that delivery rate anddelivery amount in relation to the relative movement rate of deliverydevice and catheter balloon are suitable for filling the fold resp. theinside of the fold with the active agent-containing composition of atleast 50% by volume, preferred at least 70% by volume and especiallypreferred at least 85% by volume.

Filling of one fold is done in about from 5 to 80 seconds, preferredabout 15 to 60 seconds and especially preferred about 25 to 45 secondsin the case of a fold length of 10 mm.

The catheter balloon is in the compressed, i.e. deflated, state duringthe filling operation of the folds. An even partial or slight inflationof the catheter balloon is usually not necessary for opening the folds alittle. However, the filling of the folds can be done with a slightinflation of the catheter balloon of maximum of 10% of the desireddiameter during dilatation. Moreover, the filling of the folds can bedone with a slight expansion of the folds in that 100 kPa (1 bar)positive pressure, preferred 50 kPa (0.5 bar) positive pressure areapplied for slightly expanding the folds.

This coating method can be done of course with liquid activeagent-containing compositions but is rather suitable for oilycompositions as well as for high concentrated salt solutions.

Moreover, this method offers the advantage that more than one fold andespecially all of the folds can be coated or filled simultaneously.There, an annular arrangement of delivery devices according to thenumber of folds is arranged such that per fold one delivery device isprovided. With a small rotation the tips of the delivery devices areinserted into the folds and placed about centrally in the inside of thefold. With a relative and simultaneous movement of the delivery devicesrelative to the longitudinal direction of the folds all of the folds canbe filled simultaneously with a continuous and constant flow of activeagent-containing composition.

In coating or filling of one or all of the folds the catheter ballooncan be in perpendicular or horizontal position or in a tilted position.

If in the active agent-containing composition volatile solvents wereused then drying of the fold content can be necessary. With volatilesolvents this is done preferably due to evaporation of the volatilesolvent(s).

Then a final drying can be done, wherein the catheter balloon is rotatedin the direction of the fold openings viewed from the inside of thefolds. This method will be described in detail below.

Rotation of the catheter balloon in the direction of the fold openingscan also serve to disperse the compositions which are in the folds orresp. under the folds equally in the respective fold.

This rotation of the folded catheter balloon can be advantageousespecially in the use of oily or pasty active agent-containingcompositions to ensure an equal dispersion of the activeagent-containing composition in the folds as well as the inner surfaceof the folds.

As used herein the term “coating” relates therefore mainly to thecoating of the inner surfaces of the folds, wherein the total innerspace of the folds is usually not filled with active agent-containingcomposition resp. after drying with the remaining composition.

Contrary, the term “filling” relates to the complete filling of theinner space of the fold with active agent-containing composition.

If solvents are used which are removed by drying then usually a fillingcannot be achieved and rather a coating of the inner surfaces of thefolds exists.

If, however, substances having high boiling points, such as oil, areused as carriers or adjuvants then also a more or less complete fillingof the folds is possible as long as no appreciable amounts of volatilesubstances are present in the active agent-containing composition.

This spraying method or syringe method is especially suitable forinserting active agent-containing compositions into the folds of foldedcatheter balloons which cannot be applied to a catheter balloon viacommon dipping or spraying methods not to mention to be inserted intothe folds.

Contrary to the commonly used solid coatings on stents or catheterballoons the oily or pasty coatings and fillings offer the advantagethat these active agent-containing compositions do not get dry totallybut substantially maintain their consistency.

If at the location of the stenosed site the catheter balloon is inflatedresp. dilated then this oily or pasty composition is transferred atleast partially to the vessel wall and serves as active agent reservoirfor a sustained active agent delivery of several hours to days for thesurrounding tissue and has additionally the positive property todissolve plaque and is then biologically degraded without releasingphysiologically critical degradation products.

Spraying Method or Method of Spraying Folds:

In this method according to the invention a plurality of deliveryopenings being in series are pushed or inserted under the fold of thefolded catheter balloon and simultaneously from the plurality ofdelivery openings an active agent-containing composition is deliveredinto the respective fold.

The delivery device consists preferably of 2 to 10 nozzles or deliveryopenings which are arranged in preferably equal distance along thelongitudinal direction of the folds.

This delivery device is then inserted under the fold of the catheterballoon and the respective fold is filled or coated by simultaneousdelivery of the active agent-containing composition form the nozzles orother delivery openings.

With this coating or filling variant it is not necessary that thedelivery device is moved in the fold of the catheter balloon relative tothe longitudinal direction of the fold. Usually catheter balloon anddelivery device are fixed during the filling or coating, wherein amovement along the longitudinal direction of the fold is possible. If arelative movement is provided then the distance for the movement ispreferably not bigger than the distance between two nozzles or deliveryopenings of the delivery device.

The delivery device comprises or consists of at least 2 and of a maximumof 10 delivery openings or nozzles or the like and preferred of 3 to 6and especially preferred of 4 to 5 delivery openings or nozzles or thelike which are arranged over a distance of 10 mm preferably equally.

The delivery device has 2 to 10 nozzles of similar openings which arecapable of constantly delivering the active agent-containing compositionor constantly spraying it into the fold.

For this filling or coating method preferably medium to thin viscouscompositions or solutions of an active agent or active agent combinationare used which contain especially an alcoholic solvent.

In this method of spraying folds the catheter balloon is in thecompressed, i.e. deflated, state. An even partial or slight inflation ofthe catheter balloon is usually not necessary for opening the folds alittle. However, the filling of the folds can be done with a slightinflation of the catheter balloon of maximum 10% of the desired diameterduring dilatation. Moreover, the filling of the folds can be done with aslight expansion of the folds in that 100 kPa (1 bar) positive pressure,preferred 50 kPa (0.5 bar) positive pressure are applied for slightlyexpanding the folds.

After filling a fold the catheter balloon is rotated such that the nextfold to be coated is preferably upwards and preferably horizontally. Thefilling operation of the folds or coating operation of the folds is nowrepeated.

Depending on the consistency of the active agent-containing compositionit can be necessary to dry the previously filled fold before the balloonis rotated to fill the next fold. Drying is done preferably byevaporation of the solvent.

Moreover, it is also possible in this method to fill or to coatsimultaneously two, more than two or all of the folds of a catheterballoon if the consistency of the active agent-containing compositionenables that, i.e. that the consistency is not that liquid that thecomposition leaks from the folds which are not in horizontal position.For filling or coating of more or all of the folds a respective annulardevice of delivery devices is provided corresponding the number offolds, placed around the preferably perpendicularly arranged catheterballoon and the delivery openings are inserted by rotation under thefolds, where the simultaneous delivery of the active agent-containingcomposition takes place.

If all of the folds of the balloon are filled the final drying is done.Basically, it is of course not necessary that all of the folds of thecatheter balloon are filled wherein, however, the filling of all of thefolds is the common and preferred embodiment as during dilatation amaximum possible amount of active agent shall be transferred to thevessel wall in a minimal possible time.

After filling the last fold drying of the last folds is done, i.e. ofthe content of the last fold, preferably without vacuum under normalpressure by evaporation of the solvent.

After this pre-drying a final drying can be done which is done accordingto the invention with a rotating catheter balloon. If it is necessary ordesired a vacuum can be applied during rotation. This special dryingmethod is described in more detail after the coating methods accordingto the invention.

Rotational Drying:

As mentioned above the coated or filled catheter balloons can be driedin the rotating state after filling or coating of every fold or aftercoating of filling of all of the folds or the folds to be coated resp.to be filled if not all of the folds shall be coated of filled.

This rotational drying has several advantages. First, thereby the activeagent-containing composition is dried, and second, dispersed equally inthe folds as well as on the surface within the folds.

The rotational drying is especially suitable with the oily or viscousactive agent-containing compositions to achieve an equal dispersion ofthe composition in the respective fold.

Moreover, with the rotation of the catheter balloon vacuum can beapplied to achieve an intense drying of the active agent-containingcomposition.

In drying in vacuum, especially with viscous, high viscous or solutionswhich pass into the solid state, superheating occurs, i.e. solventresidues which are occluded in the oil or solid are spontaneouslyreleased and tear or break the coating or filling. With drying in vacuumunder simultaneous rotation this superheating is avoided and a driedcontinuous coating of the inner surface of the folds is obtained.

Moreover, the direction of rotation is decisive. The direction ofrotation is done in the direction of the fold openings when viewed formthe inner of the fold. In FIG. 2 the direction of rotation is shown andthe catheter balloon is rotated as a paddle wheel of a paddle wheelexcavator for pressing the active agent-containing composition due tothe rotational force into the inside of the fold.

Preferably the folded catheter balloon is rotated with a rotational rateof 50 to 500, preferred 150 to 300 rotations per minute.

Depending on the active agent which is to be inserted into the folds ordepending on the consistency of the active agent-containing compositionwhich is to be inserted under the folds of a catheter balloon thesuitable coating method according to the invention can be selected.

The fold spraying method is preferably suitable for thin viscous tomedium viscous active agent-containing compositions while the pipettingmethod is preferably suitable for light viscous, medium viscous to lighttough viscous compositions and the spraying method can be usedespecially well for medium viscous, viscous to high viscouscompositions.

The term “viscosity” relates to the dynamic viscosity [η]:

$\lbrack\eta\rbrack = {\frac{kg}{m \cdot s} = {{{Pa} \cdot s} = \frac{Ns}{m^{2}}}}$

The spraying method can be used preferably with thick viscouscompositions. Preferred are viscosities at room temperature in the rangeof oils (olive oil: 10² mPa s), honey (10³ mPa s), glycerine (1480 mPas) or syrup (10⁵ mPa s). Of course, this method works also with thinviscous solutions having η≦10² mPa s.

The pipetting method can be used preferably with medium viscouscompositions. Preferred are viscosities at room temperature in the rangeof preferred 0.5 mPa s to 5000 mPa s, more preferred in the range of 0.7mPa s to 1000 mPa s, more preferred in the range of 0.9 mPa s to 200 mPas and especially preferred in the range of 1.0 mPa s to 100 mPa s. Inthis viscosity range are compositions of oils, contrast agents and/orsalts which are diluted with common solvents especially alcohols. Thepipetting method can be used within a very broad viscosity range.

The fold spraying method can be used preferably with thin viscouscompositions. Preferred are viscosities at room temperature in the rangeof preferred 0.1 mPa s to 400 mPa s, more preferred in the range of 0.2mPa s to 100 mPa s and especially preferred in the range of 0.3 mPa s to50 mPa s (water: 1.0 mPa s; petroleum: 0.65 mPa s; pentane: 0.22 mPa s;hexane: 0.32 mPa s; heptane: 0.41 mPa s; octane: 0.54 mPa s; nonane:0.71 mPa s; chloroform: 0.56 mPa s; ethanol 1.2 mPa s; propanol 2.3 mPas; isopropanol: 2.43 mPa s; isobutanol: 3.95 mPa s; isotridecanol: 42mPa s).

Moreover, it was found surprisingly that a composition comprising atleast a contrast agent and at least an antiproliferative,anti-inflammatory, antiphlogistic, cytostatic, cytotoxic,antiangiogenic, anti-restenotic or antithrombotic active agent and atleast an alcohol as solvent is especially well suitable for the coatingresp. filling of the folds of catheter balloons.

Intentionally, no polymer was used as active agent carrier which wasdifficultly to insert into the folds of the catheter balloon by thecoating method according to the invention, which partially jammed thefolds such that during dilatation of the folded catheter balloon anunequal opening of the folds and an unequal active agent deliveryoccurred.

In the syringe method for filling the folds of a folded catheter balloonpreferably a precision nozzle or cannula is pushed under the fold andthe mixture to be inserted is syringed into the fold, wherein preferablythe nozzle or cannula is moved along the fold or with stationary nozzleor cannula the folded catheter balloon is moved in the longitudinaldirection of the fold. This method enables a very precise and accuratecoating of each fold resp. of the whole folded catheter balloon. Aneventually used solvent evaporates or is removed under vacuum.

If the mixture or solution to be inserted has a consistency such that itcan flow into the folds then the folded catheter balloon is positionedhorizontal with one fold upwards or preferred tilted from 5 to 25degrees such that the syringe or nozzle at the lower end of the foldedcatheter balloon can be set at the fold opening and that the mixtureflows independently into the fold and fills it totally.

With these salt solutions having high salt content preferably water isused solvent as water does not react with the balloon material and doesnot damage it. As soon as the mixture has a consistency that it cannotleak from the fold anymore the folded catheter balloon is rotated andthe next fold is filled until usually all of the 4 to 6 folds of theballoon are filled. Folded catheter balloons are preferred coated in thecompressed state, wherein some special embodiments of folded catheterballoons can also be coated in the expanded state.

Such a coating method comprises the steps:

-   -   a) providing a folded catheter balloon    -   b) placing one fold of the balloon in a horizontal or up to 25        degrees tilted position,    -   c) setting the syringe opening at the fold opening facing the        head end of the balloon,    -   d) executing a relative movement of syringe opening and folded        catheter balloon in the longitudinal direction of the fold,    -   e) filling the fold during the movement operation with a mixture        of an active agent and a salt and/or an ionic contrast agent in        a suitable solvent,    -   f) if necessary, drying the mixture which is present in the fold        up to a degree which prevents leaking of the mixture from the        fold,    -   g) rotating the balloon for 360° divided by the number of folds,    -   h) repeating steps b) to g) until all of the folds are filled,        and    -   i) drying the mixtures in the folds until the mixture hardens.

If thin liquid mixtures are used then in step c) the syringe opening isset at the foot end and without relative movement according to step d)the fold is substantially filled due to capillary forces.

The present invention relates also to a method of opening narrowedvessel passages especially of cardiovascular vessels by short timedilatation. In this method during a maximum of 50 seconds, preferred amaximum of 40 seconds, more preferred a maximum of 30 seconds andespecially preferred a maximum of 20 seconds a catheter balloon withoutstent is expanded and compressed again to a diameter of smaller than the1.5 time starting diameter in the compressed state, wherein during thisoperation the vessel is only over expanded to a maximum of 10% of itsdiameter in the not narrowed state and per mm² balloon surface at least20% of the active agent contained is delivered and mostly transferred tothe vessel wall.

There, the transfer of the active agent preferably does not take placein pure form but in a matrix which at least within one hour afterdilatation functions as active agent reservoir and delivers additionalactive agent to the vessel wall before it is dissolved or degraded.

Thus, this method is characterized in that in a possibly short time apossibly large amount of active agent is transferred locally andselectively to the vessel wall of a narrowed vessel site and that withinthe following 30 to 60 minutes a local active agent reservoir is ensuredwhich is then dissolved or degraded.

For this method especially paclitaxel and paclitaxel derivatives as wellas rapamycin proved as suitable.

Another method according to the invention relates to coating of catheterballoons with oily polymerizable substances. This method comprises thesteps:

-   -   a) providing a catheter balloon (not folded catheter balloon),    -   b) providing a mixture which consists of at least 50% by weight        of oily substances with at least one multiple bond and which        contains at least an active agent,    -   c) applying a lubricant to the surface of the catheter balloon        which substantially prevents the adhering of the oily substances        on the surface of the catheter balloon,    -   d) applying the oily mixture on the lubricant resp. the        lubricant layer on the catheter balloon,    -   e) rotating the catheter balloon during the coating step d),    -   f) initiating the polymerization via light, oxygen or radical        initiators up to a not hard but elastic polymer layer,    -   g) eventually repeating the coating steps d) to f).

According to the herein disclosed methods catheter balloons can beselectively coated or filled within the folds such that the presentinvention relates to catheter balloons coated or filled in the foldswhich can be obtained according to the herein described methods.

The catheter balloons used are in the not dilated state in folds whichform an accessible inner space that protects the substances containedtherein. Possible forms of folded catheter balloons are described forexample in WO 03/059430 A, WO 94/23787 A or EP 0 519 063 B1.

It is state of the art to use a folded catheter balloon and to insert apharmacological active agent also into the folds of such a balloon.However, a method for a selective and exclusive and also completefilling of the folds is not known. The methods described in the citeddocuments are coating the balloon in the expanded state and insert acertain amount of the active agent with deflation in the folds, whereinthe residual surface of the catheter balloon which is not in the foldsis also coated.

The methods according to the invention selectively coat resp. fill thefolds of the catheter balloon in the not expanded, i.e. folded, state.The catheter balloons coated or filled according to the invention areprovided preferably for the cardiovascular field but can be used alsofor opening of all luminal structures, such as urinary passages,gullets, trachea, biliary tract, renal tract, small and large intestine,and especially of blood vessels within the whole body including brain,duodenum, and pylorus.

Thus, the coated or filled catheter balloons are especially suitable forpreventing, reducing or treating stenoses, restenosis, arteriosclerosis,atherosclerosis and all other forms of a vessel occlusion or a vesselnarrowing of passages or openings.

Moreover, the catheter balloons coated according to the invention areespecially suitable for the treatment of in-stent restenosis, i.e. forthe treatment of a renewed vessel narrowing within an already implantedstent which is preferably not bioresorbable. With suchlike in-stentrestenosis the implantation of another stent within an already existingstent is especially problematic as usually the vessel can be dilated bythe second stent to an only unsatisfying extent. Here, the applicationof an active agent via balloon dilatation offers an ideal possibility oftreatment as this treatment can be repeated several times if necessary,and from a therapeutic aspect is able to achieve the same or clearlybetter results than the new implantation of a stent.

Moreover, the catheter balloons coated or filled according to theinvention are especially suitable for the treatment of small vessels,preferably small blood vessels. Vessels having a vessel diameter smallerthan 2.5 mm, preferred smaller than 2.2 mm are referred to as smallvessels.

DESCRIPTION OF FIGURES

FIG. 1 shows a folded catheter balloon having four folds in the notdilated state, wherein a fold is being filled via a spraying nozzle witha composition of contrast agent, active agent and solvent.

FIG. 2 shows a folded catheter balloon which is completely filled in allof the four folds in the not expanded state, wherein the compositionwithin the folds is dried during the rotation of the folded catheterballoon resp. during the solvent is removed.

EXAMPLES Example 1

A common folded catheter balloon having four folds is filled in thefolded state with a composition of iopromid, which is commerciallyavailable as a solution under the trade mark Ultravist®, paclitaxel,glycerine and ethanol by means of a spraying nozzle.

The composition contains 0.150 g of iopromid, 0.300 g of paclitaxel,0.220 g of glycerine and 1.130 g of ethanol.

In each fold about 174 μg-621 μg of the composition is inserted.

After filling of all of the folds the folded catheter balloon is rotatedfor 1 minute in the direction of the fold openings and dried over night.

In total 696 μg-2484 μg of the dried composition were inserted portionedin four folds.

Example 2

About 10 mg of KMnO₄ are dissolved in 500 μl of water and as much PVP aspossible is added. The mass is distributed on a polypropylene substrateand dried over night at room temperature.

From this brittle mass 4.5 mg are dissolved in 0.5 ml of chloroform or0.6 ml of methanol or 0.8 ml of DMSO. Not dissolved particles can befiltered off. To this solution 100 μg of paclitaxel are added and afteraddition of 12.0 μg of linseed oil the resulting solution is sprayed by4 nozzles being in series with a distance of 2 mm to each other equallyinto a fold via the fold spraying method described above.

After coating the first fold in the horizontal state the coating isdried without vacuum and the balloon comprising four folds is rotatedabout 90 degrees to coat the next fold which is above.

After coating all of the folds drying in vacuum is done under rotationof the catheter balloon according to the rotational drying methoddescribed above.

Example 3

Paclitaxel (250 mg) or rapamycin (250 mg) or a combination of paclitaxel(150 mg) and rapamycin (150 mg) is dissolved or suspended in an aqueousmedium having an ethanol proportion of about 5% by volume and at a pHvalue from 4 to 5 and then mixed with a solution of phosphatidylserineand phosphatidylcholine in the weight ratio of 50:50.

A liposomal formulation is formed in which the active agent or theactive agent combination is included in the vesicles.

The extraction of the liposomes from the aqueous solution is done byultra filtration, wherein an extraction of the liposomes is notmandatory.

The extracted liposomes or the liposomal aqueous solution is filled intoa cavity and filled into a fold via the pipetting method describedabove, wherein a capillary in an angle of about 40 degrees is set at thedistal end of the fold. The catheter balloon is positioned horizontaland the fold to be coated lies above. Due to capillary forces thecomposition draws itself into the fold within about 48 seconds. Beforethe composition reaches the proximal end of the fold the capillary isremoved such that also the composition which is present at the settingpoint of the capillary is drawn into the fold.

The coated catheter balloon is then dried at air and then finally driedby the rotational drying method described above.

Example 4

400 mg of trapidil are mixed with 1 ml of safflower oil andsimultaneously inserted into the four folds of a folded catheter balloonvia the syringe method described above.

The delivery openings of the delivery device are set at the distal endof the respective fold and moved in the fold with a rate of 1 cm perminute in the direction of the proximal end while a continuous flow ofan oily trapidil solution is delivered into the fold.

Drying of the coated or filled folds is not necessary. Each fold wasfilled with about 1.5 mg of oily trapidil composition.

Example 5

300 mg of rapamycin are dissolved in 1 ml of acetic acid ester and mixedwith 200 mg of EPA (5,8,11,14,17-eicosapentaenoic acid). By addingethanol the viscosity can be adjusted such that a sprayable mixtureresults.

By the fold spraying method described above all of the 6 folds of afolded catheter balloon are simultaneously coated. The spraying deviceis comprised of an arrangement of in total 6 rows of respectively threespraying nozzles. The rows of respectively three spraying nozzles aresupported on a rotational frame and can be inserted individually intothe respective fold of the folded catheter balloon.

If the rows of spraying nozzles are properly placed the activeagent-containing composition is delivered from each nozzle under therespective fold.

The catheter balloon is preferably in a perpendicular position and thethree nozzles of a spraying row have a distance of 3 mm to each other.

After coating of the folds what can be done also in intervals the coatedfolds are dried at air under normal pressure and at room temperature andif necessary can be dried further at a temperature of 50° C. to 70° C.under normal pressure.

The folded catheter balloon was coated in the folds with totally 76 mgof solids.

Example 6

A solution of 250 μg of paclitaxel in a mixture of ethanol, n-butanoland ethyleneglycol in the volume ratio of 50:25:25 is prepared and tothis solution 200 μg of vitamin A are added.

This composition is then filled into a delivery device having in total 4cannules. Each of these four cannules is set at one of the four folds ofa folded catheter balloon in a sharp angle of about 30 degrees and thefour folds are simultaneously filled via the pipetting method describedabove.

After filling the catheter balloon is slowly rotated and simultaneouslyvacuum is applied and the rotational rate is increased with increasingvacuum for a short period of up to 1,200 rotations and the content ofthe fold is dried according to the rotational drying method describedabove.

Example 7

Borage oil or linseed oil and paclitaxel are mixed with each other inthe weight ratio of 80 to 20 and dissolved in the mixing ratio of 1:1 inchloroform or DMSO such that a viscous composition is obtained.

This composition is filled via the syringe method described above in afold of a folded catheter balloon having in total 5 folds. Therefore thecatheter balloon is fixed and rotated such that the needle of thedelivery device can be inserted into the fold to be filled. The needleis inserted at the proximal end of the catheter balloon into the fold upto about the middle and during a time of about 50 seconds the needle ismoved continuously in the longitudinal direction of the fold while acontinuous flow of viscous active agent-containing composition isdelivered into the fold.

The average coating mass of the composition per fold can be between 0.4and 2.8 mg depending on the design of the fold. In the present case theaverage coating mass of the composition per fold is about 0.8 mg in thedried state.

After filling all of the 5 folds the catheter balloon is dried underusing the rotational drying method described above.

The folded catheter balloon was filled resp. coated with totally about4.0 mg of dried composition.

Example 8

500 μg of paclitaxel is dissolved in 1 ml of anhydrous ethanol and 0.4ml of acetic acid and filled into the folds of a catheter balloon viathe pipetting method described above.

Subsequent drying is done after evaporation of the solvent according tothe rotational drying method described above.

After coating and drying about 10 μg of paclitaxel are present in eachfold.

Example 9

200 μg of paclitaxel are dissolved in 0.5 ml of ethanol and 0.5 ml ofDMSO and 0.1 ml of acetic acid. Moreover, a solution of 350 μg ofpotassium acetate in ethanol—water is prepared in the volume ratio of90:10. The potassium acetate solution is added to the paclitaxelsolution and the solvents can evaporate until the first components startprecipitating or the composition starts to get cloudy or a mediumviscous composition is obtained.

This composition is inserted into the folds of the catheter balloon viathe syringe method or the pipetting method described above. According tothe invention the folds can be filled individually or in series or canalso be filled simultaneously together. After evaporation of the solventthe final drying is done according to the rotational drying method asdescribed above.

Example 10a

500 μg of rapamycin and 25 mg of iopamidol are dissolved in 1 ml ofethanol.

This solution can be inserted in the present form into the folds of thecatheter balloon via the fold spraying method described above, whereinthe folds can be coated individually or simultaneously as describedabove.

Drying is done preferably via the rotational drying method describedabove.

Example 10b

The solution from example 10a is adjusted to a viscosity of 10³ to 10⁴mPa·s by adding propyleneglycol and/or glycerine.

The as-obtained composition is inserted into the folds according to thepipetting method described above, wherein the folds can be filledindividually after each other or simultaneously together.

Final drying is done preferably via the rotational drying methoddescribed above.

Example 10c

The solution from example 10a or from example 10b is adjusted to aviscosity of above 10⁴ mPa·s by adding an oil selected from the groupconsisting of linseed oil, flax oil, hempseed oil, corn oil, walnut oil,rape oil, soy bean oil, sun flower oil, poppy-seed oil, safflower oil,wheat germ oil, safflower oil, grape-seed oil, evening primrose oil,borage oil, black cumin oil.

The as-obtained composition is inserted into the folds of the catheterballoon via the spraying method as described above, wherein the foldscan be filled individually after each other or simultaneously together.

Final drying, if necessary, is done preferably via the rotational dryingmethod described above.

1. Method of coating or filling the folds of a folded catheter ballooncomprising the following steps: a) providing a composition comprising atleast a contrast agent and at least an antiproliferative,antiinflammatory, antiphlogistic, cytostatic, cytotoxic, antiangiogenic,anti-restenotic or antithrombotic active agent and at least an alcoholas solvent; b) inserting the composition comprising at least a contrastagent and at least an antiproliferative, antiinflammatory,antiphlogistic, cytostatic, cytotoxic, antiangiogenic, anti-restenoticor antithrombotic active agent and at least an alcohol as solventselectively into the folds of the folded catheter balloon by means of asyringe device, wherein only the folds of the folded catheter balloonare coated or filled selectively and the surface of the folded catheterballoon outside the folds is not coated; c) drying the compositioncomprising at least a contrast agent and at least an antiproliferative,antiinflammatory, antiphlogistic, cytostatic, cytotoxic, antiangiogenic,anti-restenotic or antithrombotic active agent and at least an alcoholas solvent by removing the solvent via evaporation or under reducedpressure.
 2. Method according to claim 1, wherein a syringe nozzle isused as syringe device which is inserted into the folds of the foldedcatheter balloon and the folds are filled under pressure with thecomposition comprising at least a contrast agent and at least anantiproliferative, antiinflammatory, antiphlogistic, cytostatic,cytotoxic, antiangiogenic, anti-restenotic or antithrombotic activeagent and at least an alcohol as solvent.
 3. Method according to claim1, wherein the folded catheter balloon is coated or filled in thecompressed or deflated state or at maximum 10% inflated state.
 4. Methodaccording to claim 1, wherein two or more or all of the folds of thefolded catheter balloon are filled or coated simultaneously.
 5. Methodaccording to claim 1, wherein after the filling or coating of one ormore folds of the folded catheter balloon it is rotated in the directionof the fold openings.
 6. Method according to claim 1, wherein thecomposition contains at least an alcohol as solvent selected from thegroup comprising: methanol, ethanol, isopropanol, n-butanol,iso-butanol, t-butanol, ethyleneglycol, propyleneglycol,1,3-propanediol, butyleneglycol, 1,3-butanediol, 1,4-butanediol,glycerin, 1,2,3-butanetriol, 1,2,4-butanetriol and1,2,3,4-butanetetraol.
 7. Method according to claim 1, wherein thecomposition contains at least a contrast agent selected from the groupcomprising: x-ray contrast agents, iodine-containing contrast agents,contrast agents having a 1,3,5-triiodobenzene nucleus, nephrotropicx-ray contrast agents having low osmolarity, amidotrizoic acid,iothalaminic acid, iotrolan, iopamidol, iodoxaminic acid, diatrizoicacid, iomeprol, iopromid, desmethoxyacetyl-iopromid (DAMI),5-amino-2,4,6-triiodophthalic acid-(2,3-dihydroxypropyl)-amide (ATH). 8.Method according to claim 1, wherein the composition contains at leastan oil and/or at least a fatty acid selected from the group comprising:linseed oil, flax oil, hempseed oil, corn oil, walnut oil, rape oil, soybean oil, sun flower oil, poppy-seed oil, safflower oil, wheat germ oil,safflower oil, grape-seed oil, evening primrose oil, borage oil, blackcumin oil, algae oil, fish oil, cod-liver oil, taririnic acid, ximeninicacid, stearolinic acid, 6,9-octadeceninic acid, pyrulinic acid,crepenynic acid, heisterinic acid, ETYA, linoleic acid, γ-linolenicacid, dihomo-γ-linolenic acid, arachidonic acid, α-linolenic acid,stearidonic acid, EPA, DPA, DHA, meadic acid, stellaheptaenic acid,taxolic acid, pinolenic acid, sciadonic acid, myristoleic acid,palmitoleic acid, petroselinic acid, oleic acid, vaccenic acid,gadoleinic acid, gondoinic acid, erucinic acid, nervonic acid, elaidinicacid, t-vaccenic acid, laurinic acid, myristinic acid, palmitinic acid,margarinic acid, stearinic acid, arachinic acid, behenic acid,lignocerinic acid, 6,8-dithianoctanoic acid, γ-linolenic acid, α-liponicacid.
 9. Method according to claim 1, wherein the at least oneantiproliferative, antiinflammatory, antiphlogistic, cytostatic,cytotoxic, antiangiogenic, anti-restenotic or antithrombotic activeagent is selected from the group comprising: abciximab, acemetacin,acetylvismione B, aclarubicin, ademetionine, adriamycin, aescin,afromoson, akagerine, aldesleukin, amidorone, aminoglutethemide,amsacrine, anakinra, anastrozole, anemonin, anopterine, antimycotics,antithrombotics, apocymarin, argatroban, aristolactam-AII, aristolochicacid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin,azathioprine, azithromycin, baccatine, bafilomycin, basiliximab,bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol,biolimus, bisparthenolidine, bleomycin, bombrestatin, Boswellic acidsand derivatives thereof, bruceanoles A, B and C, bryophyllin A,busulfan, antithrombin, bivalirudin, cadherins, camptothecin,capecitabine, o-carbamoyl-phenoxy-acetic acid, carboplatin, carmustine,celecoxib, cepharanthin, cerivastatin, CETP inhibitors, chlorambucil,chloroquine phosphate, cictoxin, ciprofloxacin, cisplatin, cladribine,clarithromycin, colchicine, concanamycin, coumadin, C-type NatriureticPeptide (CNP), cudraisoflavone A, curcumin, cyclophosphamide,cyclosporine A, cytarabine, dacarbazine, daclizumab, dactinomycin,dapson, daunorubicin, diclofenac, 1,11-dimethoxycanthin-6-one,docetaxel, doxorubicin, daunomycin, epirubicin, epothilones A and B,erythromycin, estramustine, etoposide, everolimus, filgrastim,fluoroblastin, fluvastatin, fludarabine,fludarabine-5′-dihydrogenphosphate, fluorouracil, folimycin, fosfestrol,gemcitabine, ghalakinoside, ginkgol, ginkgolic acid, glycoside 1a,4-hydroxyoxycyclophosphamide, idarubicin, ifosfamide, josamycin,lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone,nimustine, pitavastatin, pravastatin, procarbazin, mitomycin,methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan,topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase,exemestane, letrozole, formestane, SMC proliferation inhibitor-2ω,mitoxantrone, mycophenolate mofetil, c-myc antisense, b-myc antisense,β-lapachone, podophyllotoxin, podophyllic acid 2-ethylhydrazide,molgramostim (rhuGM-CSF), peginterferon α-2b, lanograstim (r-HuG-CSF),macrogol, selectin (cytokine antagonist), cytokinin inhibitors, COX-2inhibitor, NFkB, angiopeptin, monoclonal antibodies which inhibit themuscle cell proliferation, bFGF antagonists, probucol, prostaglandins,1-hydroxy-11-methoxycanthin-6-one, scopoletin, NO donors,pentaerythritol tetranitrate, sydnonimines, S-nitrosoderivatives,tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone,ethinylestradiol, medroxyprogesterone, estradiol cypionates, estradiolbenzoates, tranilast, kamebakaurin and other terpenoids which areapplied in the therapy of cancer, verapamil, tyrosine kinase inhibitors(tyrphostins), paclitaxel, derivatives and analoga of paclitaxel,6-α-hydroxy-paclitaxel, 2′-succinylpaclitaxel,2′-succinylpaclitaxeltriethanolamine, 2′-glutarylpaclitaxel,2′-glutarylpaclitaxeltriethanolamine, 2′-O-ester of paclitaxel withN-(dimethylaminoethyl)glutamide, 2′-O-ester of paclitaxel withN-(dimethylaminoethyl)glutamidhydrochloride, taxotere, macrocyclicoligomers of carbon suboxide (MCS), mofebutazone, lonazolac, lidocaine,ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine,hydroxychloroquine, sodium aurothiomalate, oxaceprol, β-sitosterin,myrtecaine, polidocanol, nonivamide, levomenthol, ellipticine, D-24851(Calbiochem), colcemid, cytochalasin A-E, indanocine, nocadazole, S 100protein, bacitracin, vitronectin receptor antagonists, azelastine,guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and-2, free nucleic acids, nucleic acids incorporated into virustransmitters, DNA and RNA fragments, plasminogen activator inhibitor-1,plasminogen activator inhibitor-2, antisense oligonucleotides, VEGFinhibitors, IGF-1, active agents from the group of antibiotics,cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamycin,penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole,enoxaparin, desulphated and N-reacetylated heparin, tissue plasminogenactivator, GpIIb/IIIa platelet membrane receptor, factor Xa inhibitorantibody, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase,streptokinase, warfarin, urokinase, vasodilators, dipyridamol, trapidil,nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACEinhibitors, captopril, cilazapril, lisinopril, enalapril, losartan,thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ,histamine antagonists, serotonin blockers, apoptosis inhibitors,apoptosis regulators, p65, NF-kB, Bcl-xL antisense oligonucleotides,halofuginone, nifedipine, tocopherol, tranilast, molsidomine, teapolyphenols, epicatechin gallate, epigallocatechin gallate, leflunomide,etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline,triamcinolone, mutamycin, procainimide, retinoic acid, quinidine,disopyramide, flecainide, propafenone, sotolol, natural andsynthetically obtained steroids, inotodiol, maquiroside A,ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone,dexamethasone, non-steroidal substances (NSAIDS), fenoprofen, ibuprofen,indomethacin, naproxen, phenylbutazone, antiviral agents, ayclovir,ganciclovir, zidovudin, clotrimazole, flucytosine, griseofulvin,ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents,chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin,barringtogenol-C21-angelat, 14-dehydroagrostistachin, agroskerin,agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,4,7-oxycycloanisomel acid, baccharinoids B1, B2, B3 and B7, tubeimoside,bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin,tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptaticacid A, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A andB, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B,13,18-dehydro-6-alpha-senecioyloxychaparrin, taxamairin A and B,regenilol, triptolide, cymarin, hydroxyanopterin, protoanemonin,cheliburin chloride, sinococuline A and B, dihydronitidine, nitidinechloride, 12-beta-hydroxypregnadien-3,20-dion, helenalin, indicine,indicine-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin Aand B, larreatin, malloterin, mallotochromanol,isobutyrylmallotochromanol, maquiroside A, marchantin A, maytansin,lycoridicin, margetine, pancratistatin, liriodenine, bisparthenolidine,oxoushinsunine, periplocoside A, ursolic acid, deoxypsorospermin,psycorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin,sphatheliachromen, stizophyllin, mansonine, strebloside,dihydrousambaraensine, hydroxyusambarine, strychnopentamine,strychnophylline, usambarine, usambarensine, liriodenine,oxoushinsunine, daphnoretin, lariciresinol, methoxylariciresinol,syringaresinol, sirolimus, rapamycin, somatostatin, tacrolimus,roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine,vincristine, vindesine, teniposide, vinorelbine, trofosfamide,treosulfan, temozolomide, thiotepa, tretinoin, spiramycin,umbelliferone, desacetylvismione A, vismione A and B, zeorin.
 10. Methodaccording to claim 9, wherein the at least one antiproliferative,antiinflammatory, antiphlogistic, cytostatic, cytotoxic, antiangiogenic,anti-restenotic or antithrombotic active agent is selected from thegroup comprising: paclitaxel, derivatives and analogues of paclitaxel,6-α-hydroxy-paclitaxel, 2′-succinylpaclitaxel,2′-succinylpaclitaxeltriethanol-amine, 2′-glutarylpaclitaxel,2′-glutarylpaclitaxeltriethanolamine, 2′-O-ester of paclitaxel withN-(dimethylaminoethyl)glutamide, 2′-O-ester of paclitaxel withN-(dimethylaminoethyl)glutamidehydrochloride, taxotere.